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Nocebo Effect Leads to Switched Patients Reporting Greater Disease Severity, Poorer Quality of Life vs Nonswitched Patients


A survey of patients with rheumatoid arthritis found that those who had switched to an adalimumab biosimilar reported higher disease severity, poorer treatment adherence, and poorer quality of life compared with patients who stayed on the reference product, highlighting the dangers of the nocebo effect.

A survey of physician and patients that compared reported outcomes between patients with rheumatoid arthritis (RA) who received the adalimumab reference product and those who had switched to an adalimumab biosimilar found reports of higher disease severity, poorer treatment adherence, and poorer quality of life in the group who switched to a biosimilar.

The authors, from the Adelphi RA Disease-Specific Programme, AbbVie, and the University of Oxford, said rheumatologists should be aware of the potential negative impact of nonmedical switching, and use effective communication to help prevent negative outcomes due to the nocebo effect.

Since the patent for the originator tumor necrosis factor alpha inhibitor adalimumab (Humira; AbbVie) expired in 2016 in the United States and 2018 in Europe, 7 adalimumab biosimilars have been approved to treat RA. Although trials have shown that switching to a biosimilar does not negatively affect efficacy or safety, the authors noted that some unsuccessful switches have been attributed to the nocebo effect, a worsening of symptoms due to a patient’s negative perceptions. They added that lower biosimilar retention rates in open-label compared to double-blind switch trials suggests the nocebo effect might reduce biosimilar retention rates.

The nocebo effect may be driven by a reluctance to switch away from a medication the patient is satisfied with, insufficient communication from providers regarding biosimilars, a provider’s lack of confidence in biosimilars, or a perception that the biosimilar is a lower-quality medication.

The Adelphi RA Disease-Specific Programme is a point-in-time survey of physicians and their patients with RA who had either remained on the adalimumab reference product or switched to a biosimilar in France, Germany, Italy, Spain, and the United Kingdom. Rheumatologists in the survey reported switching patients to a biosimilar mainly for financial reasons (67%). Other reasons included a formulary-driven switch (24%) or insurance restrictions (17%).

Physician-reported outcomes were analyzed for 385 patients (n = 160 nonswitchers and 225 switchers), and patient-reported outcomes were analyzed for 140 patients (n = 51 nonswitchers and 89 switchers). Although physicians were satisfied with treatment in both groups, their reports suggested disease activity was more likely to improve in non-switchers (68%) compared to switchers (26%), and less likely to worsen (1% vs 9%, respectively).

The authors said physicians reported that disease activity remained stable for the majority of switchers, but “worsened for a few.” However, they noted that most switchers in the survey had mild disease when they first started treatment, whereas most nonswitchers had moderate or severe disease. “Thus, for switchers there was less scope for improvement and more scope for worsening, which may explain our results,” they said.

Patients in both groups reported being satisfied with their treatment. When patients were asked, “How often do you not get your RA medicine because they cost too much money?” there was no difference between groups.

However, switchers reported forgetting to take their medication more frequently than nonswitchers. Also, patient surveys indicated poorer quality of life (EQ-5D Visual Analogue Scale) and greater activity impairment (Work Productivity Activity Index) in switchers compared to nonswitchers.

The authors concluded that nonmedical switching in real-world clinical practice in RA may result in “unforeseen outcomes,” potentially due to the nocebo effect. Since “negative impact from a nocebo response may impact a patient’s treatment journey and ultimately potential cost savings,” they made recommendations for mitigating the nocebo effect, in particular increasing “awareness among prescribers and patients of the strict regulatory evaluation, similar safety and efficacy of biosimilars to their reference product, and enhanced prescriber–patient communications.”


Taylor PC, Gonzalez YS, Clark R, Faccin F, Howell O. Outcomes following adalimumab bio-originator to biosimilar switch-a comparison using real-world patient- and physician-reported data in European countries. Rheumatol Ther. 2023;10(2):433-445. doi:10.1007/s40744-022-00526-w

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